Steroidal 4, 6-dien-3-ones having a substituted methyl group at c6 and process for producing same



ABSTRACT OF THE DISCLOSURE New steroidal 4,6-dien-3-ones, particularly of the androstane and pregnane series, having a CH X substituent on C wherein X is an anion such as cyano-, thiocyanato-, selenocyanato-, azido-, nitro-, and phthalimido-, produced by reaction of the corresponding 6-halomethyl steroids with a metallic salt of the formula MX, where X is defined above.

This invention is for improvement in or relating to organic compounds and has particular reference to new steroidal 4,6-dien-3-ones with a substituted methyl group at C In our copending US. applications Nos. 514,676 filed Dec. 17, 1965, and 523,247 filed Jan. 27, 1966, there are described steroidal 6-halomethyl-4,6-dien-3-ones including the partial formula Oil! CHzHal (where Hal is F, Cl, Br and I) and processes for their preparation.

We have now made the important discovery that the halogen atom present in such steroidal 6-halomethyl-4,6- dien-3-ones including the partial Formula II above may be replaced without rearrangement to give products including the partial Formula I below. This is a significant and surprising discovery as allylic structures, as will be known to those skilled in the art, often undergo structural rearrangements when submitted to substitution reactions. We have also made the discovery that some of the novel 6-substituted steroidal 4,6-dien-3-ones including the partial Formula I below can have biological properties which render them of value in the art. In addition, such 6-substituted steroidal 4,6-dien-3-ones including the partial Formula I below are of value as building blocks for the construction of novel hormonally active structures and thus have a technical importance in their own right as intermediates.

Products of the present invention are believed to have active biological properties of the type possessed by analogous known steroids. Thus compounds including the partial Formula I below where X is CN or N may show qualitative similarity in their biological properties to the corresponding 6-methyl analogues. Thus for example derivatives of l7ot-acyloxyprogesterone (in particular the -azidomethyl compounds .of Examples 3 and 11) have claudogenic properties and are of value in the control of fertility in the human and veterinary field.

Derivatives of corticoidal types are known to have United States Patent anti-endotoxic activity. Compounds including the partial Formula I where X is N or are particularly of value as intermediates due to the presence of these highly reactive groups which are known to be capable of entering into further reactions.

It is accordingly an object of the present invention to provide new 6-(substituted methyl) steroidal 4,6-dien-3- ones including the partial formula Orr 1 CHzX (I) where X is derived from the anion of a weak acid and is selected from the group consisting of --CN, -SCN, SeCN, N NO and where M is K, Na, Li or Ag and X is as hereinabove defined.

The process is carried out in solution or suspension in a dry organic solvent when the following reaction occurs:

MX 0% M. Halogen ll CI-I Halogen after which the products of the invention may be isolated and purified by methods known to those skilled in the art.

The process of the present invention may be applied to a wide variety of steroidal compounds of the androstane, l9-norandrostane, pregnane and 19-norpregnane series which, in addition to the 6-substituted 4,6-dien-3- one present in rings A and B, may also be substituted by Hydroxyl groups and esterified and etherified derivatives thereof in such positions as C C C C C C C C C and C including such groups as 16- hydroxymethyl and the condensation products of 16a, l7ocand 17a,2l-glycols with carbonyl components.

Carbonyl groups in such positions as C C C C 17, C18 and 20- Carbalkoxy groups in such positions as C C C and in the side-chain.

Cyano groups in such positions as C C and C Alkyl groups and in particular methyl groups in such a) positions as C C C C C and ethyl groups in such positions as C Alkenyl and alkynyl groups and in particular vinyl, allyl, ethynyl, trifiuoropropynyl, trifluorovinyl and chloroethynyl groups at C Methylene and ethylidene groups in such positions as 11 C16, is ir and 17- Lactone, ether and spiroketal groups and in particular spirolacetone groups including at C etheric groups at C and bridging C and C and spiroketal groups including the sapogenin side-chain.

Fluorine atoms in particular at C Unsaturated linkages including carbon-carbon doublebonds in such positions as C C C C C C and 17(20)- The process of the present invention may be applied to the 6-halomethyl-4,6dien-3-0ne compounds derived from the following steroids and their acyl derivatives: testosterone and 19-n0r derivatives thereof Z-methyltestosterone and 19-nor derivatives thereof 17ot-methyltestosterone and 19-nor derivatives thereof 9( l1)-dehydro-17a-methyltestostcrcne and 19-nor derivatives thereof 17a-propynyl, 7a-chlorethynyl, 17a-trifiuoropropynyl, l7a-trifluorovinyl testosterone and 19-nor derivatives thereof 17a-acyloxyprogesterones and 19-nor derivatives thereof 9(11)-dehydro-17u-acyloxyprogester0nes 16-methyl-17a-acyloxyprogesterones 9( l1)-dehydro-16-methy1-17u-acy1oxypr0gesterones 1G-methylene-17a-acyloxyprogesterones 9(11)-dehydro-16-methylene-17ot-aeyloxyprogesterones l7tx-acyloxy-1o-ethylideneprogesterones 16a,17a-dimethylmethylenedioxyprogesterone 9(11)-dehydro-16 x,17a-dimethylrnethylenedioxyprogesterone cortisone 16-rnethylcortisone 21-methylcortisone 16-methylenecortisone 16a-hydroxy cortisone and the (16u,l7oc)-21Ctii01lid6 therehydrocortisone 16-methylhydrocortisone 21-methylhydrocortisone 16methylenehydrocortisone 16whydroxyhydrocortisone and the (16a,17a)-acetonide thereof 17a,21-dihydroxypregna-4,9(11)-diene-3,20-dione 16 methyl-17a,21-dihydroxypregna-4,9(11)-diene-3,20-

dione 21-methyl-17a,21-dihydroxypregna-4,9(11)-diene-3,20-

dione 16-methylene-17a,21-dihydroxypregna-4,9(11)-diene- 3,20-dione 16a-hydroxy-17a,21-dihydroXypregna-4,9(11)diene-3 20-dione and the (16,17)-acetonide thereof 21-hydroxypregna-4,17 (20 -dien-3-one 11-ox0-2l-hydroxypregnat, 1 7 (20) -dien-3one 11,21-dihydroxypregna-4, 17 (20) -dien-3-one 9(11)-dehydro-21-hydroxypregna-4,17(20)-dien-3-one 3-oXopregna-4, 17 (20) -dien-21-oic acid (esters) 3,11-dioxopregna-4,17 (20) -dien-21-oic acid (esters) 11-hydroxy-3-oxopregna-4,17(20) -dien-21-oic acid (esters) 9( 1 1 -dehydro-3-oxopregna-4,17 (20) dien-21-oic acid (esters) progesterone 16-methylprogesterone 1 l-oxoprogesterone 9(1l)-dehydroprogesterone zliosgenone 21-methylprogesterone Hot-cyano-17,6-hydroxyandrost4-en-3-one 16 (a and fl)-hydroxytestosterone and 19-1101 derivatives 16-methyl-16,17-dehydroprogesterone l-cyano-progesterone 16-carb alkoxyprogesterones lG-hydroxymethylprogesterone 3-(3-oxo-17B-hydroxyandrost)-4-en-17a-yl) propionic acid testololactone The 9a-fill0r0 derivatives of the above 11fi-hydroxy and 11-oxo-steroids.

Following is a description by way of example of methods of carrying the invention into effect.

Example 1.17a-acetoxy-6-cyanomethyl-lfi-methylene pregna-4,6-diene-3,20-dione 00.118 Me 0Ac 17fl-acetoxy-6-bromomethy1-19-norandrosta--4,6-dien-3- one, and

-acetoXy-6-bromomethylandrosta-4,6-dien-3-one, and

17wacetoXy-6-bromomethylpregnar,6-diene-3,20-dione,

and

21-acetoXy-6-bromomethyl-11/3,17a-dihydroxypregna-4,6-

diene-3,20-dione, and

6-bromomethy1-16a,17a-isopropylidenedioxypregna-4,6-

diene-3,20-dione is productive of 17;?-acetoxy-G-cyanomethyL19-norandrosta-4,6-diene-3- one, and 17B-acetoxy-6-cyanomethylandrosta-4,6-dien-3-one, and 17a-acetoxy-6-cyanomethylpregna-4,6-diene-3,20-dione,

and 21-acetoxy-6-cyan0methy1-11p,17u-dihydroxypregna-4,6-

diene-3,20-dione, and 6-cyanomethy1-16a,17a-isopropy1idenedioxypregna-4,6-

diene-3,20-di0ne.

Example 2.17u-acetoxy-16-rnethylene-6-thiocyanatomethylpregnat,6-diene-3,20-dione COMB Mel ZHzSCN A mixture of 17:: acetoxy-G-bromomethyl-16-methylenepregna-4,6-diene-3,20-di0ne (0.2 g.), potassium thiocyanate (0.2 g.) and acetone (15 ml.) was stirred at room temperature for 15 minutes and then diluted with water.

. Crystallisation of the precipitated solid from ethanol gave 170; aeetoxy-l6-methylene-6-thiocyanato methylpregna- 4,6-diene-3,20-dione, M.P. 207.5 C. decomp, [M l40 (e., 0.7 in chloroform), k 281 m (6, 22,100).

Similar treatment of a stoichiometric equivalent amount of the 6-bromomethyl steroidal starting materials listed at the end of Example 1 is productive of 17B-acet0xy-6-thiocyan-atomethyl-l9-norandrosta-4,6-dien-3-one, and 21-acetOXY-llflljot dihydroxy-6-thioeyanatomethylpregna-4,6- diene-3,20-dione.

Example 3 .17u-acetoxy-6-azidomethyl-1G-methylenepregna-4,6-diene-3,20-dione CO.Me Me '---0Ac i CH3 C HzNa 17p-aeetoxy-6-azidomethyl-l9-norandrosta-4,6-dien-3- one, and

17 8-acetoxy-6-azidomethylandrosta-4,6-dien-3-one, and

21-aeetoxy-6-azidomethyl-1 1,8,17u-dihydroxypregna-4,6-

diene-3,20-dione, and

6-azidomethyl-16a,17a-isopropylidenedioxypregna-4,6-

diene-3,20-dione.

Example 4.-l7ot-acetoxy-16amethylene-6-phthalimidomethylpregna-4,6-diene-3 ,20-di0ne A suspension of 17a-aeetoxy-6-brornomethyl-l6-methylenepregna-4,6-diene-3,20-dione (0.96 g.) and potassium phthalimide (0.5 g.) in dimethylformamide 10 ml.) was stirred at room temperature for 30 minutes, by which time the steroid had dissolved. The mixture was poured into water to give a precipitate of l7tx-acetoxy-l6-methylene 6 phthalimidomethylpregna 4,6 diene-3,20-dione xmax, 219 (6, 43,400), 239.5 (a, 14,100) and 282 my. (6, 22,300).

Similar treatment of a stoichiometric equivalent amount of the 6-bromomethyl steroidal starting materials listed at the end of Example 1 is productive of 17B-aeetoxy-6-phthalimidomethyl-19-norandrosta-4,6-

dien-3-one, and

17p-acetoxy-6-phthalimidomethylandrosta-4,6-dien-3- one, and

17a-aeetoxy-6-phthalimidomethylpregna-4,6-diene-3,20-

dione, and

21-aeetoxy-1 Iii,17a-dihydroxy-6-phthalirnidomethylpregna-4,6-diene-3,20-dione.

Example 5.17a-aeetoxy-16-methylene-6-selenocyanatomethylpregna-4,6-diene-3,20-di0ne o 0 .Me

A mixture of 17a-acetoxy-6-bromomethyl-16-methylenepregna 4,6 diene 3,20 dione (0.2 g.), potassium selenocyanate (0.25 g.) and acetone (10 ml.) was heated under reflux for 5 minutes and then diluted with water. Crystallisation of the precipitated material from ethanol gave 17t .-acetoxy 16 methylene-6-selenoeyanatomethylpregna-4,6-diene-3,20-di0ne as needles, M.P. 205 C-, decomp., [(11 l30 (e., 0.7 in chloroform), A 282 mp. (e, 20,900).

Similar treatment of a stoichiometric equivalent amount of the 6-bromomethy1 steroidal starting materials listed at the end of Example 1 is productive of 17fi-acetoxy-6-selenocyanatomethyl-l9-norandrosta-4,6-

dien-3-one, and

17a-acetoxy-6-selenocyanatomethylpregna-4,6-diene-3,20-

dione, and

21-aeetoxy-1 1/3, 1 7a-dihydroxy-6-selenocyanatomethy1- pregna-4,6-diene-3,20-dione, and

16a,l7a-isopropylidenedioxy-6-selenocyanatomethylpregna-4,6-diene-3,20-dione.

Example 6.17wacetoxy-16-methylene-6-nitr-ornethylpregna-4,6-diene-3,20-dione A mixture of l7a-acetoxy-G-laromomethyl-16-Inethylenepregna-4,6 liene-3,20-dione (1 g.), sodium nitrite (1 g.) and N-methyl-2-pyrrolidone (15 ml.) was stirred at room temperature for 75 minutes. The mixture was then diluted with ether and washed with water. Evaporation of the ether solution left a residue which was crystallised from ethanol to give 17u-a cet-oxy-16-methylene-6-nitromethylpregna-4,6-diene-3,20-dione as prism-s, M.P. 251.5 C. decon1p., [M 104 (e., 0.3 in acetone), A 277 m (6, 23,900).

Similar treatment of a stoichiometric equivalent amount of the five 6-bromomethyl steroidal starting materials at the end of Example 1 is productive of 17fl-acetoxy 6 nitromethyl-19-n-0randrosta-4, 6-dien-3- one, and 17,6-aeetoxy-6-nitromethyland-rosta-4;6-dien-3-one, and

7 17a acetoxy 6-nitromethylpregna-4,6-diene-3,20-dione,

and 21 acetoxy-l1p,17a-dihydroxy-6-nitromethylpregna-4,6-

diene-3,20-dione, and 160:, 17a isopropylidenedioxy-6-nitromethylpregna-4,6-

diene-3,20-dione.

Example 7.17(3-acetoxy-6-thiocyanatomethylandrosta- 4,6-dien-3-one A0 Me Example 8.17,8-acetoxy-6-cyanomethylandrosta-4,6- dien-3-one A mixture of 17,8-acetoxy-6-bromomethylandrosta-4,6- -dien-3-one (0.3 g.) and potassium cyanide (0.15 g.) in dimethylformamide (3 ml.) was stirred for 5 hours at room temperature. The product was isolated with dichloromethane, and crystallised from ethanol to give 17/3- acetoxy 6-cyanomethylandrosta-4,6-dien-3-one, needles, M.P. 163 C., [a] +335 (c. 0.2 in chloroform), A 278 mu (6, 23,300).

Example 9'.'17a-acetoxy-6-thiocy anatomethylpregnai,6- diene-3,20-dione W Ji A mixture of 17a-acetoxy-6-bromomethylpregna-4,6- diene-3,20-dione (0.2 g.) and potassium thiocyanate (0.15 g.) in acetone (2 ml.) was stir-red for 30 minutes at room temperature. Water was added, and the product purified from ethanol. 17a-acetoxy-6-thiocyanatomethylpregna-4,6-diene-3,20-dione formed prisms, M.P. 91 C., [06113 11 (0., 0.8 in chloroform), k a 281 m (E, 19,500).

Example 10.-16a,17a-isopropylidenedioxy-6-thiocyanatomethylpregna-4,6-diene-3 ,20-dione (:0 Me I I CHzSCN A mixture of 6-bromornethyl-16a,17a-isopropylidenedioxypregna-4, 6-diene-3,20-dione (0.15 g.) and potassium thiocyanate (0.1 g.) in acetone (1 ml.) was warmed for 5 minutes at 45 C. Water was added, and the product purified from ethanol to given 16oz,17oc-iSOprOPY1idel16dioxy 6-thiocyanatomethylpregna-4,6-diene-3,20-dione, as plates, M.P. 184 C., [a] +20 (C., 0.8 in chloroform), x zsi me (E, 22,300

Example 11.17a-ace-toxy-6-azidomethylpregna-4,6- diene-3 ,ZO-dione A mixture of 17a-acetoxy-6-bromomethylpregna 4,6- diene-3,20-dione (0.2 g.) and sodium azide (0.2 g.) in N-methyl 2 pyrrolidone (2 ml.) was stirred for 4 hours at room temperature. The product was isolated with ether, and crystallised from ethanol to give acctoxy-6- azidomethylpregna 4,6 diene 3,20-dione prisms, M.P. C., [M +13 (c., 0.4 in chloroform), k 279 ma (5, 23,200).

Example 12.-16a,l7ot-isopropylidenedioxy-6-phthalimidomethylpregna-4,6-diene-3,20-dione M (1130 --o M \l/ e I Ride 0 Me 0N A suspension of 6 bromomethyl 160:,l7oc-iSOPIO- pylidene-dioxypregna 4,6 diene 3,20 dione (l g.) and potassium phthalimide (0.5 g.) in dimethylformamide (10 ml.) was stirred for 1 hour at room temperature. The mixture was poured into water, and the product collected, dried, and purified by chromatography on alumina. Elution of the column with benzene-chloroform gave 160:, 174x F isopropylidene-dioxy 6 phthalimidomethylpregna- 4,6 diene 3,20 dione which separated from benzenehexane as solvated crystals, M.P. l40150 C. (decomp.), [(11 4-134 (C., 1.1 in chloroform), k 220 (e, 41,800), 240 (6, 13,300) and 283 m (6, 20,200).

A6 Me HzSeCN Example 14.21-acetoxy-6-azidomethyl-l 118, 17a-dillY- dr0xypregna-4,6-diene-3 ,20-dione OHaOAc CO --0rr HO 1 No i l O: I

CHzNs A mixture of 21 acetoxy 6 bromomethyl-llfi, 17adihydroxypregna 4,6. diene 3,20 dione (0.2 g.) and sodium azide (0.2 g.) in N-methyl 2 pyrrolidone (2 ml.) was stirred for 4 hours at room temperature. The product was isolated with ether, and crystallised from ethanol to give 21 acetoxy 6 azidomethyl 116,170- dihydroxypregna 4,6 diene 3,20 dione, prisms, a 279 III/4 (6, 23,200).

Example 15.-21acetoxy-6-thiocyanatomethyl-l 15,170:-

dihydroxypregna-4,6-dienc-3,20-dione A mixture of 21-acetoxy 6 bromomethyl 115,170:- dihydroxypregna 4,6 diene 3,20 dione (0.2 g.) and potassium thiocyanate (0.15 g.) in acetone (2 ml.) was stirred for 30 minutes at room temperature. Water was added, and the product purified from ethanol. 21-acetoxy- 6 thiocyanatomethyl 11,8,l7a dihydroxypregna 4,6- diene 3,20 dione formed prisms, A 281 m (5, 19,500).

Example 16.-2 1 -acet0xy-6-selenocyanatomethy1-1 1B, 17a-dihydroxypregna-4,6-diene-3,20-dione (EHzSBCN A mixture of 21-acetoxy 6 bromomethyl 115,170:- dihydroxypregna 4,6 dien 3 one (0.3 g.) and potassium selenocyanate (0.3 g.) in acetone (2 ml.) was stirred for 10 minutes at room temperature. Addition of water gave a solid which was crystallised from ethanol to give 2l-acetoxy 6 selenocyanatomethyl 115,170 dihydroxypregna 4,6 diene 3,20 dione, needles, A 283 Ill L (e, 20,700).

We claim:

1. 17a-Acetoxy-6-azidomethyl 16 methylenepregna- 4,6-diene-3,20-dione.

2. 17a-Acetoxy-6-azidomethylpregna 4,6 dime-3,20- dione.

3. A process for the preparation of a compound selected from the group consisting of pregnane and androstane 4,6-dien-3-one derivatives having a CH X substituent on C where X is derived from the anion of a weak acid and is selected from the group consisting of CN, SCN, SeCN, N NO and which process comprises reacting a corresponding compound selected from the group consisting of 6-halomethyl pregnane and androstane 4,6-dien-3-ones wherein halo is F, Cl, Br or I with a metallic salt of the formula MX where M is K, Na, Li or Ag and X is as hereinabove defined.

4. A process as claimed in claim 1 wherein the process is carried out in solution or suspension in a dry organic solvent.

References Cited Burn et al., Chemistry and Industry, March 1966, p. 497 relied on.

ELBERT L. ROBERTS, Primary Examiner. 

